The promise of the Food and Drug Administration's Quality by Design (QbD) initiative is that manufacturers able to demonstrate
a high degree of process understanding and control will gain from more flexible regulatory oversight, while also boosting
confidence that their products are safe, effective, and high in quality. To achieve these goals, the FDA has launched several
initiatives to demonstrate how QbD can support real-world management of product risks and more flexible regulatory approaches.
The FDA's efforts to modernize good manufacturing practices (GMPs) and to promote quality manufacturing on a global basis
have gained new momentum, moreover, from recent crises involving adulterated and contaminated biopharmaceuticals and their
"Quality by Design is not just a buzz word," commented Moheb Nasr, director of Office of New Drug Quality Assessment (ONDQA) in the Center for
Drug Evaluation and Research (CDER), when speaking at the Drug Information Association annual meeting in June. QbD, he said,
can improve product design, increase process understanding, support a more formal approach to quality risk management, encourage
the use of modern manufacturing and analytical technologies, and promote continual improvement. Such approaches offer flexibility
to adopt modern manufacturing methods to ensure quality, while enhancing efficiency and reducing manufacturing costs.
PILOT FOR BIOLOGICS
To apply these concepts more specifically to biotech manufacturing, CDER has launched a pilot initiative offering more individualized
examination of QbD initiatives submitted in market applications for biotech therapies. The FDA announced the program in July,
calling for manufacturers to voluntarily provide chemistry, manufacturing, and controls (CMC) information in an expanded change
protocol that describes the implementation of QbD and risk management approaches for large molecules. CDER's Office of Biotechnology
Products (OBP) will manage the pilot, which will assess five original biologic license applications or new drug applications
and 10 supplements. Ideally, the candidate products have been monitored by OBP through the product development and testing
process and have benefited from early discussions between the manufacturer and FDA reviewers about R&D issues. Several manufacturers
have indicated interest in participating and should be submitting applications and supplements for pilot review over the next
The stated aim of the OBP pilot is to define clinically relevant attributes for complex products and to link these approaches
to the manufacturing process. The FDA and manufacturers have used comparability protocols to describe specific tests and acceptance
criteria to ensure that a manufacturing change will not produce negative effects. The expanded protocols will describe QbD
approaches and critical quality attributes as applied more broadly to multiple unit operations.
Although many QbD principles apply equally to small molecules and biologics, assessing relevant attributes is "a much greater
challenge for complex pharmaceuticals," the FDA stated in announcing the pilot (Federal Register, vol. 73, No. 128, July 2, 2008, p. 37973). Quality control often is more difficult with biotech products because they are
hard to characterize, and manufacturing processes are more complex and variable.
The pilot should provide information that can help the FDA implement a QbD, risk-based approach for complex products and to
develop further guidance for industry. By examining QbD approaches taken by individual manufacturers, the FDA hopes to gain
more evidence that such innovations can reduce process variability and support the production of consistent therapies that
meet quality attributes.
The OBP pilot builds on a similar initiative that has examined how manufacturers apply design space and control strategies
to drug manufacturing. ONDQA launched a CMC pilot program in 2005 that offered a more individual review of drug applications
and supplements featuring QbD approaches. So far, ONDQA has reviewed and approved eight applications; three were still under
review as of July, and one more application remained to be submitted. The pilot applications have presented examples of how
design space and process knowledge can be captured at an operational level and relate to normal operating ranges, to equipment,
and to scale.